ArticlesDocetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial
Introduction
Lung cancer is the leading cause of cancer deaths worldwide.1 Most patients are diagnosed with advanced or metastatic disease2 and although about 70% of patients initially achieve clinical remission or disease stabilisation with first-line platinum-containing therapy, nearly all have disease progression and need second-line therapy.2, 3 Currently approved second-line treatments in non-small-cell lung cancer (NSCLC) consist of monotherapy with docetaxel, erlotinib, or pemetrexed.2, 3
As part of efforts to further improve treatment for patients with advanced NSCLC, more than 15 large randomised phase 3 studies have been done in the past 10 years, but only the BR214 and TAX3175 trials have shown an improvement in overall survival. Several studies of new agents have failed to show significant improvement in overall survival in the second-line setting (appendix pp 7–9). Therefore, there is still a high unmet need for new effective second-line treatments for patients with NSCLC.
Nintedanib (formerly BIBF 1120; Boehringer Ingelheim, Ingelheim, Germany) is a potent, oral angiokinase inhibitor that targets the pro-angiogenic pathways mediated by VEGFR1–3, fibroblast growth factor receptors (FGFR) 1–3, and platelet-derived growth factor receptors (PDGFR) α and β.6 Additionally, receptor kinases of RET, FLT3, and the Src family are also inhibited (data available from authors on request).6 Preclinical studies with nintedanib have shown sustained (>30 h) blockade of VEGFR2 in vitro, and delay or arrest of tumour growth in xenograft models of human solid tumours.6 In phase 1/2 clinical trials, nintedanib showed a manageable safety profile and antitumour activity in patients with solid tumours, including NSCLC.7, 8 Limited drug–drug interactions based on its pharmacokinetic profile and absence of interaction with CYP450 enzymes allows combination of nintedanib with cytotoxic chemotherapies, such as docetaxel or pemetrexed.9, 10 The combination of nintedanib with pemetrexed has been investigated in LUME-Lung 2, a phase 3 trial in the second-line treatment of patients with non-squamous NSCLC.11, 12
We present the results of the LUME-Lung 1 study, a phase 3 trial that assessed the efficacy and safety of the combination of nintedanib and docetaxel in patients with advanced NSCLC progressing after first-line chemotherapy.
Section snippets
Patients
We did this study at 211 centres in 27 countries (23 European countries, China, South Korea, India, and South Africa). Adult (≥18 years) patients with histologically or cytologically confirmed stage IIIB/IV recurrent NSCLC (all histologies) who had received one previous chemotherapy regimen were enrolled. Only patients with relapse or failure of one previous first-line chemotherapy regimen were allowed to enter the study. In the case of recurrent disease one additional previous regimen was
Results
Patients were enrolled between Dec 23, 2008 and Feb 9, 2011. Of the 1773 patients screened, 1314 were randomised (655 to docetaxel plus ninetedanib, 659 to docetaxel plus placebo) and comprised the intention-to-treat population (figure 1). The main reason for exclusion after screening was the presence of newly detected brain metastases. Of the 1314 randomised patients, 1307 went on to receive at least one dose of study drug, and comprised the safety population (figure 1). As of the data cutoff
Discussion
Docetaxel plus nintedanib significantly improved PFS independently of histology in patients with advanced recurrent NSCLC who had progressed following first-line chemotherapy, and significantly prolonged overall survival of patients with adenocarcinoma, including patients with poor prognosis (ie, those who had progressed within 9 months of start of first-line therapy). Adverse events that were substantially more common in the docetaxel plus nintedanib group than the docetaxel plus placebo group
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